tbuckley/cabot-search huggingface dataset:
Oncomine Dx Express CE-IVD liquid biopsy assay for non-small cell lung cancer: Performance review and analytical validation.
Authors: Jeoffrey Schageman
Journal: Journal of Clinical Oncology (2023)

e21218 Background: Clinical diagnostics assays for oncology are becoming more readily available due to the advancement and democratization of Next-Generation Sequencing (NGS). Additionally, liquid biopsy can be used in NGS to detect genetic variants in circulating tumor DNA and RNA. Liquid biopsy is a less invasive option compared to traditional biopsy methods for early detection and continuous monitoring of cancer treatment outcomes. Here, we discuss screening of over 3,500 non-small cell lung cancer (NSCLC) samples, and the analytical validation of the Oncomine Dx Express Test (ODxET) and Genexus Dx Integrated Sequencer for detection of clinically significant variants in liquid biopsy samples. Methods: Our team screened over 3,500 NSCLC liquid biopsy samples in search of high priority clinical variants. Variants selected for analytical validation studies included ERBB2 exon 20 insertion, EGFR exon 20 insertion, EGFR exon 19 deletion, EGFR T790M, KRAS G12C, BRAF V600E, and RNA fusion isoforms including ALK, NTRK1/2/3, RET, and ROS1 oncogenic drivers. Over 550 screened samples were found to be positive for these variants of interest. This screening was performed on the Genexus Dx Integrated Sequencer according to the user guide. Results: The Genexus Dx Integrated Sequencer automates library preparation, sequencing, analysis, and reporting QC metrics and variant calls. Sequencing run setup is quick and straightforward, taking less than 15 minutes to start a run and just over 24 hours to go from nucleic acid to report. Limit of detection (LoD) for DNA SNVs, insertions, and deletions at 5 ng DNA input level ranged from 0.65% to 1.82% allelic frequency (AF), depending on the variant. The higher DNA input of 30 ng resulted in a lower LoD range, from 0.31% to 0.42% AF. RNA fusion and splice variant LoD at 5 ng sample input ranged from 9.9 to 19.6 molecular counts. The higher 30 ng input resulted in a lower LoD range for RNA variants as well, ranging from 6.4 to 8.0 molecular counts. In the analytical accuracy study, the false positive rate was found to be 0.2% for SNVs, 0% for insertions/deletions, and 0% for fusion targets. In the analytical reproducibility study, the average with-in run repeatability call rate (No Calls excluded) was 99.64% for DNA variants and 98.75% for RNA variants. Conclusions: Here, we demonstrated that the ODxET workflow on Genexus Dx Integrated Sequencer is a fast and efficient tool for testing clinical NSCLC liquid biopsy samples with high sensitivity and specificity.
Barriers to offering female fertility preservation to pediatric and young adult oncology patients: A national survey of pediatric hematology oncology providers in the United States and Canada.
Authors: Amanda Walker, Elan Baskir, Geoffrey Matthes, Sri Ram Pentakota, Teena Bhatla, Surabhi Batra
Journal: Journal of Clinical Oncology (2023)

e24088 Background: The American Society of Clinical Oncology (ASCO) recently updated its guidelines on fertility preservation based on similar rates of pregnancy from oocyte and embryo preservation. However, fertility preservation in female pediatric and young adults undergoing cancer treatment remains a challenge due to barriers in communication, lack of awareness and resources. Methods: A survey created using SurveyMonkey was sent electronically to all physicians who were Children’s Oncology Group (COG) members (2190), weekly for 4 weeks. Results: 304 physicians (13.8%) responded to the survey. While most providers discuss the possibility of infertility with all female patients (83%), only 43% offer fertility preservation irrespective of age. Cancer diagnosis is a key factor in the decision to offer fertility preservation to patients (63%). Ewing sarcoma (75%), osteosarcoma (69%), and bone marrow transplant candidacy (70%) are the most common diagnoses associated with physician offering of fertility preservation. It is typically offered prior to the first round of chemotherapy (53%). Seventy-five percent of providers report that insufficient time before starting chemotherapy is a major barrier to offering fertility preservation. Severity of patient illness (58%), insurance issues and high cost (19%), provider belief that it is not necessary in every patient (25%), and lack of data supporting female fertility preservation and experimental methods (16%) are other barriers which impact the decision to offer fertility preservation. Ovarian suppression (77%), cryopreservation (egg freezing) (85%), and ovarian tissue freezing (66%) are the most discussed fertility preservation options with only one out of four providers discussing freezing embryos. Only one out of five providers check Anti-Mullerian hormone (AMH) levels prior to starting cancer treatment; however, two out of five check AMH levels after completion of therapy. Most providers do not check AMH levels. Conclusions: Despite high risk for infertility among female cancer patients due to treatment and several advances that have been made in the field, the practice of offering fertility preservation is not universal due to various barriers at the physician and institutional level. Physician education and familiarity with ASCO’s newer guidelines is one way to promote a healthier dialogue and informed decision making. We also conclude that detailed guidelines and monitoring practices for diminished ovarian reserve are lacking and need further thought.[Table: see text]
Rural healthcare: A retrospective review of lung carcinoma demographics and screening in the northern Arizona healthcare system.
Authors: Jeremy Schmoyer, Tro Sekeyan, Roshini Pradeep, Neychelle Rocca
Journal: Journal of Clinical Oncology (2023)

e18696 Background: In the United States, lung carcinoma is the leading cause of cancer mortality. In 2022, the National Cancer Institute estimated 236,740 new cases of lung cancer, or 12.3% of all new cancer cases, and 130,180 deaths, or 21.4% of all cancer deaths. The risk factors for lung cancer include cigarette smoking, secondhand smoke, the non-Hispanic population, air pollution, or prior radiation therapy. The fatality and common risk factors emphasize the importance of the screening guidelines. Northern Arizona is considered an area affected by downwinder syndrome which is defined as individuals exposed to radiation from the explosion of nuclear devices at the Federal Nevada Test Site with radioactive materials being disturbed by winds. Northern Arizona Healthcare (NAH) has a large population located in these affected counties and lung cancer demographics were reviewed to observe for any variation when compared to the general population. The patients were also reviewed to determine if there were any major deficits in screening guidelines. Methods: This retrospective review included patients diagnosed with lung carcinoma based on the ICD 9 and 10 codes between 2015 to 2020 in the NAH systems. The total number of charts included 559 but 184 were excluded for the following reasons: concern for lung cancer, but not confirmed, patients located not in Northern Arizona, diagnosed prior to 2015, duplicate name but same medical record number, malignancy other than lung cancer, metastatic cancer with unknown primary, and lung cancer was eventually ruled out. The total number of patients remaining in the review was 375. Demographics and lung carcinoma screening information were obtained through NAH medical records. Results: Demographics: median age of 71 with 286 of 375 patients &gt; 65; gender 53.06% males, 46.4% female; race: 88.8% Caucasian, 4.8% Hispanic, Native American 4%, African American 2.1%, Asian 0.3%; smoking history 56.8% active, 31.4% former, 10.6% never; Lung Cancer Pathology: Adenocarcinoma 49.3%, Squamous Cell 18.9%, NSCLC (other than adenocarcinoma or squamous cell) 11.78%, Small Cell 17%, undetermined 2.7%; Lung Cancer Screening: 64.50% no screening vs 7.2% who did, 28.3% were indeterminable. Conclusions: Despite Northern Arizona being considered an area affected by downwinder syndrome, a five-year review of lung carcinoma demographics did not expose any major variation when compared to the generalized population. A limitation was molecular markers were not included and a potential area of further investigation. The review did expose deficits in lung carcinoma screening. 64% of the 375 patients were not screened for lung cancer. A formal presentation was held at NAH grand rounds to raise awareness of lung carcinoma screening guidelines. For future advancement, a collaboration with IT to develop outpatient screening alerts to optimize healthcare in rural areas.
Prevalence of pathogenic germline variants in a cohort of patients with early onset non-small cell lung cancer (EOLUNG).
Authors: Maria Jove, Mireia Gausachs, Joaquim Bosch-Barrera, Enric Carcereny, Alex Teulé, Miguel Mosteiro, Marta Pineda, Eva Tornero, Sara Hijazo-Pechero, Jose Carlos Ruffinelli, Jesús Brenes, Alejandro I. Hernandez, Claudia Fina, Elia Sais, Joan Brunet, Marta Doménech, Maria Saigi, Teresa Moran, Conxi Lazaro, Ernest Nadal
Journal: Journal of Clinical Oncology (2023)

10630 Background: Patients with early onset lung cancer might be more likely to carry pathogenic (or likely-pathogenic) germline variants (PGV) in genes associated with cancer predisposition. However, germline testing is not recommended in this population. We designed this study to determine the prevalence of PGVs in patients with early onset lung cancer. Methods: This prospective, multicenter cohort study assessed PGV in patients younger than 51 years diagnosed with non-small cell lung cancer (NSCLC) in 3 sites at the Catalan Institute of Oncology between June 2018 to May 2022. Genomic DNA was sequenced using a custom-designed NGS panel covering 164 cancer-predisposing genes and results were discussed in a multidisciplinary tumor board. Results: 138 patients were included. Median age was 45.5 (28-50) years; 49% were females; 79% were ever-smokers with a median packs-year of 24 and median age of tobacco initiation of 16 years old. Most patients had non-squamous histology (88%) and had stage IV (62%) at diagnosis. Somatic oncogenic drivers were found in 74 patients (54%): EGFR 27 (20%); ALK 22 (16%); KRAS 20 (14%); RET 3 (2%); ROS1 1 (1%); BRAF V600E 1 (1%). Only 4% had past personal history of cancer and 50% had family history of cancer in a first-degree relative, being lung and breast cancer the most common tumors. Overall, 20 patients (14%) carried PGVs involving 12 genes associated with cancer predisposition: PARK2 (n=4); SBDS (n=3); NBN (n=2); ATM (n=2); TSC1 (n=2) and BLM, FANCA, MCPH1, PMS2, POLH, SDHA, RECQL4 (n=1, each). Four patients (3%) fulfilled criteria to be referred to genetic counseling clinic. There were no significant differences in clinical and molecular characteristics among patients with PGVs compared to their counterparts (Table). Conclusions: In this prospective cohort, 14% of patients with early onset NSCLC harbored germline PGVs. As clinicopathological and genomic features were not associated with PGVs, germline testing might be considered in addition to comprehensive genomic characterization of tumor tissue in young patients with NSCLC. However, only a minority of PGVs were deemed clinically actionable.[Table: see text]
Longitudinal changes in echocardiographic variables and endothelial function to predict cardiovascular toxicities in patients with multiple myeloma receiving carfilzomib.
Authors: Hannah Johnston, Nicole Prabhu, Claire Cunningham, Jennifer H. Cooperrider, Evangelia Andreatos, Martha Gorski, Sarah Major, Brittany Wolfe, Eric Kruse, Benjamin Avi Derman, Roberto Lang, Andrzej Jakubowiak, Ajay Major, Jeanne DeCara
Journal: Journal of Clinical Oncology (2023)

e20012 Background: Carfilzomib (CFZ) is a second-generation proteasome inhibitor with activity in multiple myeloma (MM) that is associated with cardiotoxicity and dyspnea. The pathophysiology and risk factors for developing these toxicities are not well described. We are conducting a prospective observational study (NCT04827563) of longitudinal changes in cardiovascular and endothelial function among MM patients receiving CFZ. We hypothesize that baseline and longitudinal variations in cardiovascular and endothelial function correlate with development of cardiotoxicity and dyspnea in MM patients receiving CFZ. Methods: Patients with MM receiving first-time CFZ therapy are prospectively enrolled and undergo the following study procedures prior to CFZ initiation and then every 2 weeks for the first 6 weeks of CFZ therapy (C1D1, C1D15, C2D1, C2D15): 24-hour ambulatory blood pressure monitoring, echocardiography, pulse wave velocity, and EndoPAT endothelial function assessment. Patient-reported outcomes are also collected. Cardiovascular adverse events (CVAEs) and dyspnea are assessed at all timepoints, as well as at 3 and 6 months after enrollment, by CTCAE v5.0 and are adjudicated by a cardio-oncologist. Patients with endothelial dysfunction will be defined as reactive hyperemia index (RHI) &lt;1.67 via EndoPAT. Baseline variables were analyzed with unpaired t-tests and longitudinal variables were analyzed by one-way repeated measures ANOVA. Results: Ten patients have completed 6 months of follow-up. Demographic data is summarized in the table. Four patients (40%) developed dyspnea, 2 with grade 1 and 2 with grade 3 at maximum, with most patients developing dyspnea by C1D15. Two patients had ongoing grade 1 dyspnea at follow-up. Four patients (40%) developed grade 3 or higher CVAEs, most of which were grade 3 hypertension and/or grade 3 HFpEF. Baseline left ventricular mass was significantly higher in patients who developed dyspnea compared to those who did not (p=0.040). EndoPAT values were significantly different between C1D1 and C1D15 in those with CVAEs (2.28 vs 1.74, p=0.0223). NTproBNP values were also significantly different between C1D1 and C1D15 in those with dyspnea (74.5 vs 129.3, p=0.006). Conclusions: MM patients that developed dyspnea during treatment with CFZ had a higher baseline LV mass and were more likely to develop increases in NTproBNP despite preserved ejection fraction, consistent with HFpEF. This group also had a greater change in EndoPAT values suggesting that short-term alterations in endothelial function may have a role in the development of dyspnea in those who may have the anatomic substrate for HFpEF. Clinical trial information: NCT04827563 . [Table: see text]
A phase II study of surufatinib in patients with osteosarcoma and soft tissue sarcoma who have experienced treatment failure with standard chemotherapy.
Authors: Xing Zhang, Qiuzhong Pan, Ruiqing Peng, Bushu Xu, Dongchun Hong, Yi Que
Journal: Journal of Clinical Oncology (2023)

e23540 Background: Surufatinib is a multi-targeted, small-molecule tyrosine kinase inhibitor (TKI) that shows strong inhibitory effect on the activity of VEGFR-1, 2, 3, FGFR1 and CSF-1R. Here we conducted this trial to explore the efficacy and safety of surufatinib in the treatment for osteosarcoma and soft tissue sarcoma (STS) patients (pts) who have failed in standard chemotherapy. Methods: Pts with advanced osteosarcoma and STS (unresectable or metastatic), 14-70 years, and ECOG PS 0-1, are eligible. Surufatinib 300 mg q.d. is given in a 21-days schedule. Progression-free rate at 12 weeks (PFR 12weeks ) was the primary endpoint. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety (NCT05106777). Results: As of December 30, 2022, 19 pts (male, n=12; median age, 44 years [range, 23-67]; median lines of prior therapy, 2 [range, 2-5]) were enrolled. The most common histological subtypes included 3 leiomyosarcoma, 3 liposacroma, 3 epithelioid hemangioendothelioma, 2 fibrosarcoma and other. The interim analysis revealed 7 pts with stable disease (SD) and 1 pt with partial response (PR) at 12 weeks in stage 1. Recruitment was continued in stage 2 as initially planned. With 15 pts for efficacy analysis, PFR 12weeks was 60% (9 pts). Best objective response by RECIST 1.1 was complete response (CR) in 1 pt (ORR of 6.7%) and SD in 11 pts (DCR of 80%). With a median follow-up of 6.97 months (95%CI: 5.28-8.65), the median PFS was 5.7 months (95%CI: 1.07-10.30). Treatment emergent adverse events (TEAEs) were mostly mild (grade 1-2), and the most common were hypertension (80%), proteinuria (73%), hypertriglyceridemia (53%), diarrhea (47%) and hyperbilirubinemia (47%). Grade 3-4 TEAEs were recorded in 4 pts including hypertension, proteinuria, hypertriglyceridemia and hypermagnesemia. Conclusions: Surufatinib is well tolerated and have some clinical activity in advanced osteosarcoma and STS who failed standard chemotherapy. Enrollment is ongoing and updated data will be presented in the future. Clinical trial information: NCT05106777 .
Investigating the clinical relevance of RNA editing events and their derived neoantigens in patients with melanoma treated with immunotherapy.
Authors: Xiaodong Zhang, Wei Wang, Wenhao Zhou, Qicheng Lu, Tian Ding, Ligang Fan
Journal: Journal of Clinical Oncology (2023)

e21580 Background: RNA editing (RE) is a post-transcriptional modification occurring in RNA, which promotes transcriptome and proteome diversity. Peptides translated from RE sites may represent a new source of neoantigens in cancer (RE-derived neoantigens, RED-neoantigens) that could be presented on tumor surface by human-leukocyte-antigen (HLA) and recognized by specific T-cells, leading to an improved response to immune checkpoint inhibitors (ICIs). However, the clinical significance of both RE events and RED-neoantigens in melanoma patients with ICIs therapy has not been systematically characterized. Methods: The WES and transcriptome data with immunotherapy response of melanoma were obtained from the GEO and SRA database. Vardict and VEP were used to identify and annotate the somatic mutations. Polysover was applied to identify the HLA genotype. RNA editing events were identified by Reditools2 and filtered by a custom pipeline. miRTar2GO was implemented to predict the RE event whether located in miRNA targets within the 3' UTR region. NetMHCpan and NetCTLpan were used to identify and characterize RED-neoantigens. K-M survival analysis was performed on the training set to investigate the clinical relevance of RNA editing events and RED-neoantigens in melanoma patients treated with immunotherapy. The independent melanoma dataset was used to validate this clinical relevance. Results: In total, 7,116 RE events were identified, most of which were A-to-I events. 34% of RE sites in 3'UTR and 15% in 5' UTR were located in the seed regions of miRNA targets and transcription factor binding sites (TFBS), respectively, suggesting the different functional effects of the RE events. Furthermore, using our custom pipeline, 631 RED-neoantigens were identified that show a significantly greater peptide-MHC affinity, and facilitate epitope processing and presentation than wild-type peptides. Meanwhile, we found that patients exhibiting a high RED-neoantigens burden correlated with an increased OS, and a significantly higher RED-neoantigens burden was observed in responders. The area under the curve (AUC) of the RED-neoantigen was 0.831 of OS and 0.686 of responsiveness. Conclusions: The findings in this study provide a more insightful view and resource for investigating the neoantigens in cancer as well as for novel cancer immunotherapies and biomarker development.
Correlation of cardiovascular disease with racial disparities in endometrial cancer outcomes.
Authors: Mitchell Depke, Rebekah Summey, Elizabeth Hopp
Journal: Journal of Clinical Oncology (2023)

5602 Background: Survival for Black women with endometrial cancer (EC) is shorter than that for non-Hispanic White (NHW) women, with a rate ratio for mortality of 1.98 per the American Cancer Society. Cardiovascular risk factors and disease are also more prevalent in Black women than NHW women. In women with breast cancer, Black patients received less optimal management of comorbidities and experienced increased cardiovascular disease (CVD)-related mortality as compared to White women. Similar to breast cancer, we hypothesize that CVD contributes to EC mortality disparities for Black women. Methods: In this retrospective cohort study, SEER and institutional data were utilized to investigate the contribution of CVD to outcomes for Black EC patients. The primary outcome was the contribution of cardiovascular mortality to the overall survival of Black patients. Secondary outcomes included identifying rates of new cardiovascular diagnoses, renal dysfunction, and adequacy of blood pressure control. The SEER cohort was defined using SEER*Stat 8.4.0.1. Uterine cancer patients were identified from the 2020 SEER Research Data. Survival by cause of death and proportion of deaths by cause of death were analyzed. Raw and adjusted hazard ratios for cardiovascular mortality were calculated. Next, institutional data was used to investigate survival, CVD diagnoses, renal dysfunction, and HTN in EC patients. Results: The SEER cohort contained 192,465 patients. Of these, 153,878 (80.8%) were White and 19,906 (10.3%) were Black. Black race was associated with decreased survival among patients who died of cardiovascular causes (HR 1.51, 95% CI 1.4 - 1.63, p &lt; 2*10 -16 ). When adjusted for age, stage, and histology, the hazard for decreased survival remained elevated for Black patients who died of cardiovascular causes (adjusted HR 1.65, 95% CI 1.52-1.77, p &lt; 2*10 -16 ). Our institutional cohort included 1491 patients, 1263 (84.7%) White and 151 (10.0%) Black. Black patients had a relative risk of death of 1.92 (95% CI 1.38 - 2.61) compared with White patients. Among patients with CVD, the hazard for death was 2.02 (95% CI 1.39 - 2.80). Black patients had significantly higher blood pressure, creatinine, and eGFR measurements. Conclusions: Racial outcome disparities in EC are multifactorial. CVD management will become increasingly important with the use of targeted therapies including lenvatinib and trastuzumab. Our study highlights an additional area of disparity and suggests possible interventions.